It is known that many anticancer agents, e.g., vinca alkaloid, anthracycline, epipodophilotoxin, paclitaxel and docetaxel, become in effective when administered to a patient having multi-drug resistance (MDR) which has been caused by the presence of overexpressed p-glycoprotein in the patent. P-glycoprotein inhibits intracellular accumulation of the administered anticancer agent by pumping the agent out of the cell (D. W. Shen, et al., Science (1986), 232, 643-645; and Schinkel, et al., Cell (1994), 77, 491-502). Accordingly, there have been numerous attempts to enhance the bioavailability of the above-mentioned agents by incorporating therein an inhibitor of p-glycoprotein.
Since the conventional p-glycoprotein inhibitors, such as verapamil and cyclosporin A, cause serious adverse effects, e.g., blood pressure decline and immunity suppression, a number of new p-glycoprotein inhibitors such as piperidine-2-carboxylate, acridine, piperazine-2,5-dion, anthranilic acid and methanodibenzosuberan derivatives have been developed. However, such newly introduced p-glycoprotein inhibitors have been reported to have toxicity and other problems (see PCT Publication No. WO 94/07858; WO 92/12132; WO 96/20180 and 98/17648; and WO 98/22112).
Accordingly, the present inventors have endeavored to develop a p-glycoprotein inhibitor that is free from the above problems, and have found a novel compound which markedly enhances the bioavailability of anticancer agents by suppressing p-glycoprotein.